The present invention relates to a process for preparing peptide synthons. It relates more especially to a new method of a non-racemizing peptide synthesis.
It is known from certain specialized works, such as, for example, The Peptides, vol. 1, Academic Press (1979), or Principles of Peptide Synthesis, Springer (1984) to carry out peptide syntheses by condensing a peptide chain in which the acid terminus is activated (E) and the amine terminus is protected (P) with another peptide chain in which only the acid terminus is esterified. This synthesis is carried out in the presence of an organic base which permits neutralization of the leaving group (EOH) which is in most cases acidic. This synthesis is performed by the following reactions: ##STR1##
The base used, irrespective of its nature, causes substantial racemization of the peptide unit, either during the activation stage or during the coupling stage.
It is well known in peptide synthesis that most peptides are active only under a single diastereoisomeric form. Racemization causes a loss of activity of the products obtained after the condensation. This racemization is very detrimental to the use of the peptides because the chirally active starting materials used are often very expensive. Since the peptides are used in the pharmaceutical industry, which sets stringent analytical standards, the peptides must be purified if their synthesis produces a mixture of diastereoisomers. This purification is very costly.
As a result, industry has been seeking for a long time chemical processes which compete with the processes of extraction from natural products. Industry as sought active peptides of well defined chiral purity at a cost capable of competing with the extraction processes.
It is known, for example, to prepare peptides while inhibiting racemization to a maximum by the use of activating agents such as dicyclohexylcarbodiimide (DCC) and additives such as:
N-hydroxysuccinimide, PA0 1-hydroxybenzotriazole, PA0 N-hydroxy-5-norbornene-2,3-dicarboximide.
It is generally known to condense, without excessive racemization, amino acids which are N-protected by urethane groups. This condensation is performed by a synthesis technique that enables amino acids to be added to a peptide one by one. On the other hand, when the amine group is substituted by an acyl group, as disclosed by Miyazawa, Yamada and Kuwata, Peptide Chemistry, 69 (1982), or it forms part of a peptide chain, the degree of racemization is no longer insignificant and can reach 25%.
It is also known, from European Patent No. 184,243, to prepare silyl derivatives of amino acids or peptides using trialkylcyanosilanes, and then to couple these silyl derivatives with activated amino acids or peptides. During the silylation, there is a liberation of hydrocyanic acid, which is so toxic that it has led to the exclusion of this process from all industrial programs. Moreover, the activating agents used in the above-mentioned patent cannot be used on peptide fragments without the occurrence of substantial racemization.
Consequently, the degree of racemization varies with the amino acid, the protective group, the activating reagent and the conditions of the activation reaction. In particular, the degree of racemization can be complete when an acyl type protective group is used.